Hypertriglyceridemia

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Hypertriglyceridemia

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• John D. Brunzell, M.D. NEJM Volume
  3571009-1017 September 6, 2007 Number 10.
  Clinical Practice

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Outline

• Case Presentation
• Strategies and Evidence
• Evaluation
• Management
• Lifestyle Modification
•    Medication
•    Treatment in p'ts with DM
• Areas of Uncertainty
• Guidelines
• Conclusions and Recommendations

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Case Presentation

• A healthy 45 Y/O man is found on routine
  screening to have hypertriglyceridemia. He is a
  nonsmoker, has a reasonable diet, consumes one
  alcoholic drink per week, and exercises
  regularly. He takes no medications. His father
  died at the age of 55 years in an automobile
  accident his mother is healthy at 67 years of
  age, and he has two healthy older brothers.
• BP is normal, BMI is 28, and waist circumference
  is 96 cm.
• His fasting TG is 400 mg /dl, total cholesterol
  230 mg/dl, LDL 120 mg /dl, and HDL 30 mg /dl. His
  FPG level is 90 mg /dl. Thyroid and renal
  function are normal.
• How should this case be assessed and managed?

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The Clinical Problem

• Hypertriglyceridemia a common form of
  dyslipidemia,frequently associated with premature
  CAD, defined by the occurrence of a MI or the
  need for a coronary-artery procedure before 55
  Y/O for men and 65 Y/O for women.
• Specifically, hypertriglyceridemia correlates
  strongly with the presence of small, dense
  particles of LDL and reductions in the HDL2
  component, both of which are known to be
  associated with premature CAD.

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• Several common genetic disorders of
  hypertriglyceridemia cause premature CAD.
• familial combined hyperlipidemia
• the residual dyslipidemia in well-controlled type
  2 DM
• familial hypoalphalipoproteinemia.
• Disorders associated with premature CAD are
  common familial combined hyperlipidemia and
  familial hypoalphalipoproteinemia each affect
  about 1 of the general population, and type 2 DM
  affects more than 5.
• These three disorders have been purported(??) to
  account for up to 50 of premature CAD events,
  warrant aggressive interventions to reduce the CV
  risk.

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• One other inherited form of hypertriglyceridemia
  monogenic familial hypertriglyceridemia is
  not associated with premature CAD affects up to
  1 of the population.
• Secondary hypertriglyceridemia include untreated
  or uncontrolled DM, treatment with several
  medications (Table 1), and alcohol consumption.
• More complex forms of secondary
  hypertriglyceridemia develop with hypothyroidism,
  ESRD, the nephrotic syndrome, and HIV infection
  these disorders are not covered in this article.
• TG above 2000 mg/dl (22.6 mmol/l) always have
  both a secondary and a genetic form of
  hypertriglyceridemia.

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Strategies and Evidence Evaluation

• The evaluation of hypertriglyceridemia should
  initially focus on whether there is a family
  history of the condition or a personal or family
  history of premature CAD in addition, potential
  secondary causes (e.g., medications or untreated
  DM) should be identified.
• The presence of premature CAD in a first-degree
  relative (parent or sibling) or in a sibling of a
  parent suggests familial combined hyperlipidemia
  or familial hypoalphalipoproteinemia and
  indicates the need to consider drug therapy.

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• Xanthomas do not help distinguish the various
  hypertriglyceridemic disorders.
• BMI should be calculated, and waist circumference
  measured.
• An elevated TG level and a large waist
  circumference may be a better marker of I.R. and
  the risk of CAD than hypertriglyceridemia alone.
• A large waist circumference (defined in European
  Americans as a value greater than 40 in. 101.6
  cm for men and 35 in. 88.9 cm for women) may
  help to distinguish familial hypertriglyceridemia
  (which is not associated with central adiposity
  or an increased CV risk) from familial combined
  hyperlipidemia or familial hypoalphalipoproteinemi
  a.

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• Small, dense LDL particles are also present in
  both familial combined hyperlipidemia and
  familial hypoalphalipoproteinemia and, as noted
  above, have been associated with premature CAD.
• In p'ts with elevated TG in the absence of a
  personal or family history of clinical
  atherosclerosis, apolipoprotein B levels may help
  to distinguish familial combined hyperlipidemia
  from familial hypertriglyceridemia.
• Apolipoprotein B levels are higher in familial
  combined hyperlipidemia and lower in familial
  hypertriglycieridemia.

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• The nomograms for apolipoprotein B (Figure 1),
  developed from the third National Health and
  Nutrition Examination Survey, can be used to
  define elevated apolipoprotein B as an age- and
  sex-adjusted value above the 90th percentile.
• The current NCEP recommends the measurement of
  non-HDL cholesterol (which consists of total
  cholesterol minus HDL and includes TG-rich
  lipoprotein cholesterol) instead of
  apolipoprotein B.

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Figure 1. Apolipoprotein B Levels According to
Age and Sex.

• P'ts with the metabolic syndrome who have
  elevated levels of apolipoprotein B (gt90th
  percentile for age) have familial combined
  hyperlipidemia and should receive aggressive
  lipid-lowering therapy.
• The data, which are based on a total of 11,483
  participants in the third National Health and
  Nutrition Examination Survey (19881991), are
  from Carr and Brunzell.

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Management

• After treatment of secondary disorders and
  removal of offending medications, lifestyle
  modification and drug treatment should be
  considered in hypertriglyceridemia who is
  considered to be at risk for premature CAD
  (Figure 2).
• A major question in management is whether therapy
  should be directed solely toward reduction of TG
  or toward the modification of associated
  abnormalities of intermediate-density
  lipoprotein, LDL, and HDL .
• TG levels greater than 1000 to 1500 mg /dl (11.3
  to 16.9 mmol /l) require treatment with fibrates
  to reduce the risk of pancreatitis.
• The benefit of treating mild-to-moderate
  elevations in TG levels is less clear.

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Figure 2. Algorithm for the Diagnosis and
Management of Moderate Hypertriglyceridemia.

• After secondary causes of hypertriglyceridemia
  have been ruled out, p'ts who do not have
  clinical premature CAD should undergo evaluation,
  including family history, apolipoprotein B
  levels, and possibly apolipoprotein A-I levels,
  to distinguish genetic disorders associated with
  a risk of premature CAD (familial combined
  hyperlipidemia FCHL and familial
  hypoalphalipoproteinemia FHA) from a genetic
  disorder that is not associated with an increased
  risk of premature CAD (familial
  hypertriglyceridemia FHTG).
• The ultimate diagnosis dictates the form of
  therapy required. To convert the values for TG to
  millimoles /l, multiply by 0.01129.

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 Lifestyle Modification

• Weight loss results in a mild-to-moderate
  decrease in TG (about 22) and an increase in HDL
  (about 9), largely because of an increase in
  HDL2 (about 43). The level of small, dense LDL
  particles may decrease by as much as 40.
• Aerobic exercise of moderate intensity with high
  frequency (about 4 hours per week) has been
  associated with maintenance of improved
  cardiorespiratory fitness.
• It has also been associated with a decrease in
  intraabdominal fat, an increase in HDL levels if
  those levels were low, and a small decrease in TG
  levels.

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• Although a decrease in dietary fat can lead to
  weight loss (and associated reductions in TG
  levels), diets that are low in fat but high in
  carbohydrates may result in reductions in both
  LDL and HDL.
• A reasonable approach is to reduce foods rich in
  saturated fat and replace them with complex
  carbohydrates and monounsaturated and
  polyunsaturated fats.
• Avoid simple sugars, particularly fructose,
  associated with postprandial hypertriglyceridemia.
  
• Fructose is present in many carbonated beverages
  and fruit-juice mixes, and high-fructose corn
  syrup(????) is added to many prepared foods as a
  preservative and sweetener.

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• For p'ts with exercise limitations, the
  combination of a diet low in saturated fat and a
  regimen of walking on a daily basis is a
  lifestyle change that can usually be maintained.
• n3 fatty acids may lower TG and, according to
  some data, reduce CV events.
• Cigarette smoking is associated with an earlier
  occurrence of CAD, by about 10 years.
• Discontinuation of smoking is associated with
  improvement in lipid levels despite the weight
  gain that often follows cessation.

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• Alcohol intake is associated with a reduced risk
  of atherosclerotic CVD but also leads to an
  increase in BP and in the risk of hemorrhagic
  stroke.
• Modest alcohol intake (two drinks/day for men and
  one drink/day for women) is considered
  acceptable.
• P'ts with severe hypertriglyceridemia (TG above
  2000 mg /dl) associated with alcohol use should
  abstain.
• The limited effect in pts with TG below 500 mg
  /dl (5.6 mmol /l) should not preclude moderate
  alcohol intake(?????).

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Medication

• As noted above, no set targets for TG levels are
  clearly warranted(??) other than to reduce the
  risk of pancreatitis.
• Generally, medications are considered in p'ts
  with hypertriglyceridemia who have a personal or
  family history of premature CAD.
• When medications are used, those that
  specifically decrease the level of small, dense
  LDL particles and raise the level of HDL2
  particles are preferred (Table 2).

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• Statins are generally considered the first drug
  of choice to lower LDL in premature CAD.
• Nicotinic acid therapy, often combined with a
  statin, may be an alternative first choice in
  p'ts at risk for premature CAD. Nicotinic acid
  can reduce the level of small, dense LDL
  particles and raise HDL2 particles (Table 2).
• In the Coronary Drug Project, nicotinic acid
  resulted in a 15 reduction in the risk of MI
  among men with hypercholesterolemia who had
  atherosclerosis and decreased total mortality by
  10 at 15 years.
• In the Investigation of the Treatment Effects of
  Reducing Cholesterol (ARBITER) 2 trial, it was
  also shown to prevent the progression of carotid
  artery disease in atherosclerosis who were
  already receiving statin therapy.

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• Nicotinic acid combined other drugs effective in
  reducing progression of atherosclerosis in
  hypertriglyceridemia who are at risk for
  premature CAD.
• In a randomized study involving atherosclerosis,
  low HDL, and borderline-high TG, combination of
  nicotinic acid and simvastatin was associated
  with a slight regression of coronary stenoses,
  whereas placebo or antioxidant vitamins were
  associated with progression.
• In another study, involving men with elevated
  apolipoprotein B levels, nicotinic acid in
  combination with colestipol reduced the frequency
  of progression of atherosclerosis.
• Nicotinic acid is available in crystalline form
  and extended-release form. Flushing may be a
  bothersome side effect, but its frequency may be
  minimized by education about use.
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  gm??,??4?,????????,????????1 gm,??4
  ?????????????(Niaspan 2g)????????,????,??????

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• Fibrates also lower TG levels, but the results of
  randomized trials have been equivocal in terms of
  major outcomes, generally showing decreases in
  the rates of nonfatal MI but not in the rates of
  fatal coronary events or total mortality.
• In the Veterans Affairs High-Density Lipoprotein
  Cholesterol Intervention Trial, the use of
  gemfibrozil resulted in a significant decrease in
  the primary outcome of CHD and nonfatal MI, but
  not in the secondary outcome of fatal MI or death
  from any cause.
• In a WHO trial, the use of clofibrate in men with
  hypercholesterolemia resulted in a reduction in
  the rate of nonfatal MI, but there was no
  decrease in the rate of fatal MI or total
  mortality. Such findings raise questions about
  the use of a fibrate as a first-line drug for
  mild-to-moderate hypertriglyceridemia. GI side
  effects were also common with this therapy
  similar findings were reported in another
  randomized trial of gemfibrozil.

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Treatment in p'ts with DM

• Use of statin therapy to lower LDL levels is
  recommended for adults with type 2 DM .
• In type 2 DM, the combination of statins and
  fibrates has often been used to treat
  hypertriglyceridemia.
• However, in the Fenofibrate Intervention and
  Event Lowering in DM Trial, use of fenofibrate
  did not result in a significant reduction in the
  primary outcome nonfatal MI or fatal CHD in
  p'ts with type 2 DM.
• A reduction in the rate of nonfatal MI was offset
  by a slight increase in the rate of fatal MI.

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• Nicotinic acid may interfere with glucose
  control, not be used as a first-line drug for the
  treatment of hypertriglyceridemia in p'ts with
  DM.
• However, several trials have demonstrated that
  nicotinic acid therapy can be used in p'ts whose
  DM is well controlled, with little effect on
  glucose levels.

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Areas of Uncertainty

• Decisions about the use of drugs to prevent
  premature CAD must be based on the presence or
  absence of a family history of premature
  atherosclerosis and dyslipidemia.
• Once premature CAD has developed, secondary
  prevention with lipid-lowering therapy is
  indicated, and there is no need to differentiate
  among the types of hypertriglyceridemia.
• Optimal pharmacologic approach in premature CAD
  remains uncertain, including whether it is
  preferable to start with a statin or to begin
  with nicotinic acid and add a statin as needed.
• The role of fibrates also remains unclear.

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Guidelines

• The NCEP has specific recommendations for target
  LDL levels, but not for target TG levels.
• Treatment with fibrates is recommended for TG
  over 1000 mg /dl in order to decrease the risk of
  TG-induced pancreatitis.
• After the target level for LDL has been reached,
  the program recommends lowering TG if they are
  above 200 mg /dl (2.6 mmol /l), although there
  are no data to support this recommendation.

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Conclusions and Recommendations

• The p't described in the vignette has an elevated
  TG and a low HDL level, but his LDL is not
  elevated.
• Difficult to assess the associated risk of
  premature CAD.
• No apparent secondary cause of his
  hypertriglyceridemia, and he has no other
  apparent risk factors for premature CAD.
• A first step in evaluating p'ts with
  hypertriglyceridemia is to obtain an extensive
  family history a family history will often
  identify other relatives who might need
  lipid-lowering therapy.
• A family history of premature CAD would suggest
  familial combined hyperlipidemia or familial
  hypoalphalipoproteinemia.

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• If a p't has many adult relatives with
  hypertriglyceridemia but without clinical
  evidence of atherosclerosis, successful treatment
  might be accomplished with lifestyle
  modifications alone, including a reduced-calorie
  diet that is low in saturated fat and a program
  of regular aerobic exercise.
• If the p't has or is at apparent risk for
  premature CAD on the basis of the family history
  and appears to have familial combined
  hyperlipidemia or familial hypoalphalipoproteinemi
  a, pharmacologic therapy should be considered.
• Although the optimal therapy is uncertain, in
  such cases favor combined treatment with
  nicotinic acid and a statin.

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Lipemia Retinalis Associated with Secondary
Hyperlipidemia

• A 26 Y/O with a 6-month history of type 1 DM
  presented with weight loss and poor glycemic
  control.
• P.E. no xanthomas all vessels in the posterior
  pole and peripheral area of each eye had a creamy
  appearance (Panels A and B). The p't had no
  problems with his vision.
• Lab FPG 261 mg /dl (14.5 mmol /l normal range,
  60 to 120 mg /dl 3.3 to 6.7 mmol /l), Chol
  1086 mg /dl (28.1 mmol /l normal range, 120 to
  220 mg /dl 3.1 to 5.7 mmol /l), and TG 11,929
  mg /dl (134.7 mmol /l normal range, 50 to 149 mg
  /dl 0.6 to 1.7 mmol /l).

NEJM 2007 Volume 357e11 September 6, 2007 Number
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• DKA and secondary hyperlipidemia was diagnosed.
• No family history of hyperlipoproteinemia.
• Intensive insulin therapy and supportive care
  were provided. One week after treatment, lab.
  showed an improved lipid profile Chol 321 mg
  /dl (8.3 mmol /l) TG114 mg /dl (1.3 mmol /l)
  and FPG 68 mg /dl (3.8 mmol /l).
• Fundus showed a normal appearance of the retinal
  vessels (Panels C and D).
• Lipemia retinalis is thought to be directly
  correlated with the serum TG typically, the
  retinal findings do not occur until the TG
  reaches 2500 mg /dl (28.2 mmol /l).

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TC
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Thank you for your attention!